Review
doi: 10.1371/journal.ppat.1006351.
eCollection 2017 Jul.
Toxoplasma gondii: Entry, association, and physiological influence on the central nervous system
Oscar A Mendez
1
2
, Anita A Koshy
2
3
4
Affiliations
- PMID: 28727854
- PMCID: PMC5519211
- DOI: 10.1371/journal.ppat.1006351
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Review
Toxoplasma gondii: Entry, association, and physiological influence on the central nervous system
Oscar A Mendez et al.
PLoS Pathog.
.
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Abstract
Toxoplasma gondii is one of the world's most successful parasites, in part because of its ability to infect and persist in most warm-blooded animals. A unique characteristic of T. gondii is its ability to persist in the central nervous system (CNS) of a variety of hosts, including humans and rodents. How, what, and why T. gondii encysts in the CNS has been the topic of study for decades. In this review, we will discuss recent work on how T. gondii is able to traverse the unique barrier surrounding the CNS, what cells of the CNS play host to T. gondii, and finally, how T. gondii infection may influence global and cellular physiology of the CNS.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
(A) The blood-brain barrier (BBB) is composed of microvessels surrounded by an endothelial cell layer with tight junctions; pericytes surround the tight junctions and then astrocytic processes or endfeet provide the final layer. (B)
Toxoplasma gondii has been postulated to have 3 mechanisms for crossing the BBB. (1) Paracellular entry, in which T. gondii migrates directly through the tight junctions of the endothelial cell layer, (2) transcellular entry, in which free parasites in the vascular compartment infect endothelial cells, replicate, and then egress out of the basolateral side of endothelial cell (lysing the host cell), (3) the "Trojan horse" method, whereby an infected immune cell infiltrates the CNS, after which the parasite egresses out of the immune cell and into the brain parenchyma.
(A) After entering the CNS, T. gondii should be able to interact with different cells in the brain, including both astrocytes (orange) and neurons (beige). As the T. gondii–Cre system leads to the expression of a green fluorescent protein (GFP) in host cells injected with T. gondii protein regardless of infection status, it can help distinguish between 2 likely models for T. gondii persistence in neurons. (B) Model 1: after infiltration of the CNS, T. gondii interacts with and invades both astrocytes and neurons, causing both cell types to express GFP (green). Astrocytes clear the intracellular parasite while neurons cannot, leaving neurons as the primary host cell for persistent infection. (C) Model 2: after infiltration of the CNS, T. gondii almost exclusively interacts with and invades neurons, leading to GFP expression primarily in neurons. Neurons potentially clear some but not all invading parasites, leaving neurons as the primary host cell for persistent infection.
(A) Under normal conditions, glutamate, an excitatory neurotransmitter, is released into the synaptic cleft from the presynaptic neuron. Glutamate then diffuses across the synaptic cleft to act on glutamate receptors on the postsynaptic neuron, leading to excitation of the postsynaptic neuron. This glutamatergic signaling is terminated by uptake and recycling of synaptic glutamate by the glutamate transporter GLT-1 on surrounding astrocytes. Glutamate uptake by GLT-1 is essential to avoid excessive glutamate signaling, which can lead to postsynaptic excitotoxicity and neuronal death. After an infection, GLT-1–dependent transport into astrocytes is impaired, allowing for an increase in glutamate accumulation in the synaptic cleft, which is expected to lead to more excitation of the postsynaptic neuron. (B) Glutamate decarboxylase (GAD) is primarily found on presynaptic terminals, where it will process glutamate into γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. Once GABA is released into the synaptic cleft, it will bind onto GABA receptors on the postsynaptic neuron, which decreases the excitability of the postsynaptic neuron. In the case of infection, GAD is redistributed into the cytosol of the presynaptic neuron, which would be expected to cause improper GABA localization at synapses, leading to decreased inhibition of the postsynaptic neuron.
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